Growing evidence indicates that there is an emerging link between environmental pollution and cardiac hypertrophy, while the mechanism is unclear. The objective of this study was to examine whether phenanthrene (Phe) could cause cardiac hypertrophy, and elucidate the molecular mechanisms involved. We found that: 1) Phe exposure increased the heart weight and cardiomyocyte size of rats; 2) Phe exposure led to enlarged cell size, and increased protein synthesis in H9C2 cells; 3) Phe exposure induced important markers of cardiac hypertrophy, such as atrial natriuretic peptide, B-type natriuretic peptide, and c-Myc in H9C2 cells and rat hearts; 4) Phe exposure perturbed miR-133a, CdC42 and RhoA, which were key regulators of cardiac hypertrophy, in H9C2 cells and rat hearts; 5) Phe exposure induced DNA methyltransferases (DNMTs) in H9C2 cells and rat hearts; 6) Phe exposure led to methylation of CpG sites within the miR-133a locus and reduced miR-133a expression in H9C2 cells; 7) DNMT inhibition and miR-133a overexpression could both alleviate the enlargement of cell size and perturbation of CdC42 and RhoA caused by Phe exposure. These results indicated that Phe could induce cardiomyocyte hypertrophy in the rat and H9C2 cells. The mechanism might involve reducing miR-133a expression by DNA methylation.

Influenza A virus (IAV) infection is a complicated process. After IAVs spread to the lung, extensive pro-inflammatory cytokines and chemokines are released, which largely determine the outcome of infection. Using a single-cell RNA sequencing (scRNA-seq) assay, we systematically and sequentially analyzed the transcriptome of more than 16,000 immune cells in the pulmonary tissue of infected mice, and demonstrated that two waves of proinflammatory factors were released. A group of IAV-infected PD-L1 + neutrophils were the major contributor to the first wave at an earlier stage (day 1-3 post infection). Notably, at a later stage (day 7 post infection) when IAV was hardly detected in the immune cells, a group of platelet factor 4-positive (Pf4 +)-macrophages generated another wave of pro-inflammatory factors, which were probably the precursors of alveolar macrophages (AMs). Furthermore, single-cell signaling map identified inter-lineage crosstalk between different clusters and helped better understand the signature of PD-L1 + neutrophils and Pf4 +-macrophages. Our data characteristically clarified the infiltrated immune cells and their production of proinflammatory factors during the immunopathogenesis development, and deciphered the important mechanisms underlying IAV-driven inflammatory reactions in the lung.

No abstract

Organotin compounds such as tributyltin (TBT) and triphenyltin can induce diabetes and insulin resistance. However, the development of diabetes caused by organotins and its underlying mechanisms remain unclear. In the present study, male KM mice were orally administered with TBT (0.5, 5, and 50 μg/kg) once every 3 days for 45 days. Their body weights increased and reached a significant difference compared to the control, and the fasting blood glucose levels were significantly elevated. The fasting levels of serum insulin and adiponectin increased, while glucagon levels decreased in the animals treated with TBT. The expression of the insulin receptor (IR) signaling cascade, including IR, IR substrate, phosphatidylinositol 3-kinase, Akt, and glucose transporter 4, was inhibited both in the skeletal muscle and the liver, which might be a main reason for the hyperglycemia and hyperinsulinemia. After removing the TBT stress for 60 days, the animals which had received exposure to TBT could recover normoglycemia, accompanied with a recovery of the suppressed IR signal pathway and fasting insulin levels. However, the fasting levels of serum adiponectin and glucagon were lower than that of the control mice, which would remain a potential risk inducing the disruption of glucose homeostasis.

No abstract

There is increasing recognition of the importance of early-life environmental exposures in health disorders at later-life stages. The aim of this study was to evaluate whether early-life exposure to benzo[a]pyrene (BaP) could induce neurodegenerative syndromes at later-life stages in zebrafish. Embryos were exposed to BaP at doses of 0, 0.05, 0.5, 5, and 50 nM from early embryogenesis to 96 h post-fertilization (hpf), then transferred to clean water and maintained for 365 days. We found that BaP decreased locomotor and cognitive ability, neurotransmitter levels of dopamine, 3,4-dihydroxyphenylacetic acid and norepinephrine; and induced loss of dopaminergic neurons and resulted in neurodegeneration. Additionally, BaP increased amyloid β protein and cell apoptosis in the adult zebrafish brain. Further, DNA methyltransferase 1 (DNMT1) and DNMT3a were up-regulated in 96 hpf larvae and the adult brain. MeDIP-sequencing data of the 96 hpf larvae identified 235 differentially methylated genes in promoter, with the fold change > 1.5. Guanylate cyclase 2F (gucy2f) and dopamine receptor D4 related sequence (drd4-rs) were hypermethylation promoters, whereas zinc finger C4H2 domain (zc4h2) was a hypomethylation promoter in 96 hpf larvae and the adult brain. The mRNA levels of gucy2f and drd4-rs were down-regulated, and zc4h2 was up-regulated. Our findings suggested that the lasting modifications of DNA methylation were associated with neurodegenerative syndromes in adult zebrafish as a result of early-life BaP exposure.

The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.

Acute myeloid leukemia (AML) is caused by clonal disorders of hematopoietic stem cells. Differentiation therapy is emerging as an important treatment modality for leukemia, given its less toxicity and wider applicable population, but the arsenal of differentiation-inducing agents is still very limited. In this study, we adapted a competitive peptide phage display platform to search for candidate peptides that could functionally induce human leukemia cell differentiation. A monoclonal phage (P6) and the corresponding peptide (pep-P6) was identified. Both L- and D-chirality of pep-P6 showed potent efficiency in inducing THP-1 cells differentiation, driving their morphologic maturation and upregulating the expression of macrophage markers and cytokines including CD11b, CD14, IL-6, IL-1β and TNF-α. In the THP-1 xenograft animal model, administration of D-pep-P6 was effective in inhibiting tumor growth. Importantly, exposure to D-pep-P6 induced the differentiation of primary human leukemia cells isolated AML patients in a similar manner to the THP-1 cells. Further mechanical study suggested that D-pep-P6 induced human leukemia cell differentiation by directly activating a TLR-2 signaling pathway. These findings identify a novel D-peptide that may promote leukemia differentiation therapy.